The stilbene compound resveratrol is naturally present in grape skin and seeds and is found in particularly high concentrations in red wine. Epidemiological studies have shown that those who consume red wine have a reduced risk of vascular diseases, a phenomenon known as the French Paradox. Here, we document that pretreatment with resveratrol decreases ischemic stroke damage. Neuronal cell death in neurodegenerative conditions has been postulated to be mediated by free radical damage. Promising candidates to limit free radical-mediated damage are the endogenous antioxidant enzymes present in the central nervous system, such as catalase, superoxide dismutases, and heme oxygenases. Transcription of these cytoprotective proteins is under control of Nrf2, which plays a central role in the regulation of the cellular redox status. For example, we and other showed that heme oxygenase enzyme, which cleaves the prooxidant heme to form biliverdin/bilirubin (antioxidants), is protective. One goal would be to induce it, and of the compounds we tested, as shown in the preliminary data, resveratrol was a most potent inducer. Our preliminary data indicate that pretreatment of neurons with resveratrol was sufficient to provide neuroprotection, suggesting that cotreatment during oxidative stress is not necessary. The results so far imply that specific induction of genes under the control of Nrf2 could be a mechanism by which resveratrol exerts its neuroprotective actions in stroke. We will extend our ongoing inquiry into the beneficial effects of oral pretreatment with resveratrol against hemorrhagic stroke and determine whether it can reduce the severity of outcomes in mice subjected to the collagenase and autologous blood models of intracerebral hemorrhage (ICH). We will investigate the effect of acute and chronic daily oral administration of resveratrol on brain injury volume, brain edema, and neurobehavioral outcome deficits at different time points following hemorrhage and test whether these beneficial effects are attenuated in Nrf2 knockout mice. To further determine if resveratrol of protective in neurons and address possible cellular mechanisms of action, primary postnatal cultured neurons derived from Nrf2 knockout pups and matched controls will be pretreated with resveratrol and then tested for susceptibility to tert- butylhydroperoxide-induced free radical toxicity and heme, which is also a pro-oxidant. Notably, under pathologic conditions such as in ICH, heme reaches high toxic levels;it cannot be recycled and has to be degraded. Nrf2 can then induce various antioxidant enzymes. These results will indicate whether preconditioning of primary neurons is sufficient to afford neuroprotection and whether the effect is modulated by Nrf2. Understanding the efficacy and limitations/safety of natural compounds such as resveratrol in ischemic and hemorrhagic stroke may help the general public and healthcare providers to make informed decisions on whether resveratrol and similar bioactive extracts are efficacious as adjunct treatments for such devastating neurological diseases. It will also allow us to address possible mechanisms by which the oral consumption of the stilbene resveratrol could be neuroprotective and have the putative ability to provide the brain with cellular endogenous resistance to debilitating neurodegenerative conditions. PUBLIC HEALTH RELEVANCE: For decades, the stilbene resveratrol and red wine have been suggested as preventive medicine to strengthen the heart and the brain, but the underlying cellular mechanisms are still unclear. Our preliminary results prompted us to focus our attention on resveratrol and test the hypothesis that the pathway leading to the regulation of the transcriptional factor Nrf2 could participate in resveratrol's neuroprotective function. Using preclinical laboratory mouse models, we will determine whether prophylactic consumption of resveratrol can prevent neurological decline and brain damage following hemorrhagic stroke, thus providing new pathways by which resveratrol could provide resistance to acute neurological disorders.